4eph | pdb_00004eph

CRYSTAL STRUCTURE OF RAT CARNITINE PALMITOYLTRANSFERASE 2 IN COMPLEX with CoA-site inhibitor

spinqualitylabelsall models 4eph, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4eph is a 1 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0RK, BOG Related: 4ep9, 2rcu, 2deb, 2fyo, 2fw3, 2h4t Gene: Cpt2, Cpt-2 (Rattus norvegicus) Activity: Carnitine O-palmitoyltransferase, with EC number 2.3.1.21 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed Carnitine palmitoyl transferase 2 (CPT-2) is a key enzyme in the mitochondrial fatty acid metabolism. The active site is comprised of a Y-shaped tunnel with distinct binding sites for the substrate acylcarnitine and the cofactor CoA. We investigated the thermodynamics of binding of four inhibitors directed against either the CoA or the acylcarnitine binding sites using isothermal titration calorimetry (ITC). CPT-2 is a monotopic membrane protein and was solubilized by beta-octylglucoside (beta-OG) above its critical micellar concentration (CMC) to perform inhibitor titrations in solutions containing detergent micelles. The CMC of beta-OG in the presence of inhibitors was measured with ITC and small variations were observed. The inhibitors bound to rat CPT-2 (rCPT-2) with 1:1 stoichiometry and the dissociation constants were in the range of K D = 2-20 muM. New X-ray structures and docking models of rCPT-2 in complex with inhibitors enable an analysis of the thermodynamic data in the context of the interaction observed for the individual binding sites of the ligands. For all ligands the binding enthalpy was exothermic, and enthalpy as well as entropy contributed to the binding reaction, with the exception of ST1326 for which binding was solely enthalpy-driven. The substrate analog ST1326 binds to the acylcarnitine binding site and a heat capacity change close to zero suggests a balance of electrostatic and hydrophobic interactions. An excellent correlation of the thermodynamic (ITC) and structural (X-ray crystallography, models) data was observed suggesting that ITC measurements provide valuable information for optimizing inhibitor binding in drug discovery. Isothermal titration calorimetry with micelles: Thermodynamics of inhibitor binding to carnitine palmitoyltransferase 2 membrane protein.,Perspicace S, Rufer AC, Thoma R, Mueller F, Hennig M, Ceccarelli S, Schulz-Gasch T, Seelig J FEBS Open Bio. 2013 Apr 19;3:204-11. doi: 10.1016/j.fob.2013.04.003. Print 2013. PMID:23772395 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Carnitine palmitoyltransferase

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